Bioinspired phenolic hydrogel: A promising toolkit for inflammatory cardiovascular therapy through oxidative stress...

Atherosclerosis, driven by oxidative stress and chronic inflammation, requires advanced localized therapies targeting reactive oxygen species (ROS) and immune dysregulation. Here, we report the development of a bioinspired, phenolic-functionalized, zwitterionic chitosan hydrogel engineered for potent antioxidant therapy and macrophage modulation. The hydrogel, synthesized via a green, aqueous enzymatic crosslinking approach, exhibits strong antioxidant activity (~178 μmol Trolox equivalents/g) and efficient free radical scavenging (ABTS⁺ inhibition ~86%, hydroxyl radical scavenging ~82%). It significantly inhibits lipid peroxidation (~68% reduction in MDA levels) and foam cell formation, while promoting anti-inflammatory M2 macrophage polarization (~2.1-fold increase). Furthermore, treatment with the hydrogel markedly downregulated pro-inflammatory biomarkers including IL-6 (~72% reduction), TNF-α (~65% reduction), and CRP (~60% reduction) compared to untreated controls. The material also demonstrated excellent injectability and self-healing properties, and it maintained >90% antioxidant activity after 3 months of storage and 10 freeze-drying cycles, showing higher storage and lyophilization stability than PON1 under the tested conditions. These results highlight the hydrogel's multifunctional therapeutic potential, stability, and biocompatibility, positioning it as a promising platform for targeted, sustained antioxidant therapy in atherosclerosis management.